Composition comprising quinazoline diuretics potentiated by carbonic anhydrase inhibitors



Unite tes This invention relates to potentiated pharmaceutical compositions containing either diuretics of the 7-halo-6- sulfamyl-4-quinazolinone type, hypotensive drugs such as alkaloids of the Rauwolfia family, or both: the compositions being potentiated by a carbonic anhydrase inhibitor.

Diuretics are an important class of drugs and are used extensively to reduce or eliminate edema and other symptoms usually associated with the retention of an excessive amount of sodium ions in the body. The carbonic anhydrase inhibitors, and particularly the preferred one of the present invention, namely acetazolamide, have an effect on the excretion of sodium ions. However, carbonic anhydnase inhibitors promote the excretion of bicarbonate ions rather than chloride ions. Thus, this class of compounds has limited diuretic eiiectiveness upon repetitive administration due to the development of metabolic acidosis. In the present invention they are not used as diuretics but as potentiators of other diuretics or of hypoten-sive drugs, or both.

There are a number of diuretics which cause the excretion of sodium and chloride ions and these are sometimes referred to as saluretics. Mercurials, the classical salu-retics, often are toxic upon acute or chronic administration. Untoward reactions include local eifects at the site of injection (e.g. pain, inflammation, ecchymosis), damage to the liver, kidney or heart, and plasma electrolyte imbalance.

In more recent years various eliective saluretics have been developed, including chlorothiazide and hydrochlorothiazide. The compounds are good s-aluret-ics but, while they do not have as extreme adverse side efiects as the mercurial diuretics, still they have serious disadvantages. They tend to cause magnesium diuresis and potassium diuresis. These electrolyte disturbances may result in listlessness, weakness, apathy and cardiac malfunction.

Another new class of saluretics has been developed, namely, the 7-halo-6-sulfamyl-4-quin'azolinones. In their unreduced form the quinazolinone compounds are described in South African Patent 82/59, issued August 6, 1959. These unreduced quinazolinone compounds are effective as saluretics only when they are used in relatively large doses, for example 20 rug/kg. The compounds have a very low toxicity so that they can be used in these larger doses but in such effective doses they produce a kaluresis sufficiently severe to make them undesirable for long-cont-hiued use. As with most other drugs, diuretics show undesirable side effects in addition to those which have been set out above. The use of excessive doses is, therefore, never desirable.

A still more recent development is a new class of saluretics, namely the 1,2,3,4-tettrahydro-7-halo-6-sulfamyl-4-quinazolinones. These new saluretics are described in an article by Cohen et al., on pages 2731-35 of volume 82 of the June 5, 1960, issue of the Journal of the American Chemical Society. They are also described and claimed in a copending application of Cohen and Vaughan, Serial No. 823,806, filed June 30, 1959. The new tetuahydroquinazolinones are more potent saluretics but even they are not completely free iirom side eifects and so any means for reducing the effective dosage is desirable,

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though not as vital as with the other types of saluretics referred to above.

Some hypotensive agents such as mecamylarnine and particularly the Rauwolfia alkaloids present some problems from the standpoint of use. They also produce undesirable reactions when used in large doses, such as dizziness, mental confusion, and the like and, in the case of mecamylamine, there is some tendency to increase the excretion of magnesium. Unfortunately, one of the underlying causes of hypertension is an abnormal functioning of the kidneys. As a result the hypertension is often accompanied by edema or an excessive sodium retention, or both. Hypotensors, including those of the Rau- Wolfia family, do not correct the problem of electrolyte imbalance. In fact, in some cases they may exacerbate the symptoms.

Because of the problems accompanying many forms of hypertension, it has been proposed in the past to use diuretics; for example, mercurial diuretics with hypotensive agents such as Rauwolfia alkaloids. This combination does, in fact, relieve some of the complications presented by edema but only at the expense of further complications such as kaluresis, excessive magnesium excretion, and the like, which have been described above.

Even when hypotensive agents such as Rauwolfia alkaloids are used with greatly improved saluretics represented by the tetrahydroquinazolinones, the result, while far superior to that obtainable with other diuretics such as mercurials, unreduced quinazolinone compounds and the like, is still not ideal. The complications due to edema are largely eliminated without producing excessive kaluresis but the total dosage of the combination cannot be markedly reduced because the tetrahydroquinazolinones only augment, rather than potentiate, the antihypertensive action of the hypotensive drug.

The present invention is based on a new combination of drugs in which carbonic anhydrase inhibitors are added to diuretics of the quinazolinone type or hypotensive agents, such as Rauwolfia alkaloids, or compositions containing both, and achieve a very marked potentiation. As a result smaller doses can be used, side eliects are minimized, and compositions of the present invention open up a wide field of continuous, safe therapy. This is of great practical importance because while some hypotensive; manifestations, such as premenstrual tensions, may be temporary, in most cases the condition remains for a long period of time and may require continued therapy, even in some cases for life. It is in this field that the compositions of the present invention, which contain all three types of drug, are opening up the possibilities of longterm safe treatment with a minimum of side efiects which was not hitherto available. Even in the case of the compositions containing only the carbonic anhydrase inhibitor and the quinazolinone type of diuretic, reduction of dosage and kaluresis is of great importance.

The carbonic anhydrase inhibitors appear to be, in general, compounds which require the presence of the suliarnyl group. Of the carbonic anhydrase inhibitors, acetazolamide is Z-actyiamino 1,3,3 thiadiazole-Ssulfonamide, and methazolamide is 5-acetylamino-4-methyl-A-2,1, 2,3,4-thiadiazoline-Z-sulfonamide. Other canbonic anhydrase inhibitors include ethoxybenzothiazole-Zsulfona mide (ethoxyzolamide), 4,5-dichloro-m-benzene disulfonamide (dichlorophenarnide), p-carboxybenzene sulfonamide and psultamyl-Z-hydroxyethyl-carbonylate.

While in its broader aspects the present invention is not limited to any particular carbonic anhydrase inhibitor, the preferred one is acetazolamide and a large part of the specific disclosure to follow will deal with the use of this particular compound.

As far as the quinazolinone compounds are concerned, the present invention results in a much more dramatic 3 potentiation of the unreduced quinazolinone compounds of the South African patent referred to above, whereas the improvement in regard to the already much superior tetrahydroquinazolinones is not so marked.

The exact mechanism of the present invention is not known and it is not intended that the invention shall be limited to any theory of action as to just why potentiation results. The final result is greatly improved in all cases and it is this which constitutes the practical advance of the present invention.

Another surprising and unexpected result maybe noted. It has been proposed in the past to use acetazolamide with mercurial diuretics but it was found that this combined use was only practical if the acetazolamide were administered several hours before the mercurial diuretics. In the case of the present invention, the carbonic anhydrase inhibitor, such as acetazolamide, is mixed with a quinazolinone compound, Rauwolfia alkaloid or both and the administration is simultaneous. The marked potentiation which results greatly simplifies the treatment of patients and is an important practical advantage. It also indicates strongly that the mechanism of potentiation in the present invention is probably quite different from any interaction with mercurial diuretics although, as has been pointed out above, the exact mechanism is not known and hence the invention is not to be considered limited thereby.

The present invention may be used with any of the quinazolinones whether unreduced as those described in the South African patent mentioned above or the tetrahydro compounds, some of which are described in the above-cited article by Cohen et al. Other tetrahydroquinazolinone compounds include the iollowing: 1,2,3,4- tetrahydro-7-ohloro-2-ethyl-6-sulfamyll-quinazolinone, 1, 2,3,4-tetrahydro-7-chloro-2-butyl 6 sulfamyl-4-quinazolinone, 1,2,3,4-tetrahydro-7-chloro 2 isopropyl-6- sulfamyl-4-quinazolinone, 1,2,3,4-tetrahydro-7-chloro-2- chloromethyl-6-sulfamyl-4-quinazolinone, and the like.

Another advantage of the present invention lies in the enormous range in which the drugs can be used. For example, the proportion of the acetazolamide to the hypotensor may range from 10:1 to 100021. In the case of the 7 halo-6-sulfamyl-4-quinazolinones, the range is not critical though the preferred range is not quite so wide and varies from 1:1 to 1:5. Thus, for example, in the case of compositions containing the three drugs, acetazolamide, hypotensor, and 7 halo-6-sulfamyl-4-quinazolinone, the range of the three can vary from 10:1:10 to 1000:1z5000.

A third and practical advantage of the invention lies in the fact that the drugs can be made up in tablets which can be taken by mouth and are well tolerated by patients.

The invention will be illustrated in greater detail in conjunction with the following specific examples in which the parts are by weight unless otherwise specified.

EXAMPLE 1 The following typical formulations show carbonic anhydrase inhibitor in tablets with a typical Rauwolfia alkaloid, reserpine, and with tetrahydro-7-halo-6-sulfamyl-4-quinazolinone diuretics:

(A) A compressed A standard concave tablet form with bisecting (scored) line, containing 250 mg. acetazolamide plus 0.5 mg. reserpine:

Gm./tab.

Acetazolamide granulation 0.56900 Reserpine 0.00050 See footnote 1 under paragraph (J). (B) A compressed standard concave tablet form with bisecting line, containing 250 mg. acetazolamide plus 0.25 mg. reserpine:

Gm./tab.

Acetazolamide granulation 1 0.56900 Reserpine 0.00025 See footnote 1 under paragraph (J).

(C) A compressed standard concave tablet form with bisecting line, containing mg. acetazolamide plus 0.5 mg. reserpine:

Gin/tab. Acetazolamide granulation 0.11380 White blank granulation 2 0.05500 Corn starch 0.00500 Reserpine 0.00050 Magnesium stearate 0.00050 See footnotes 1 and 2 under paragraph (.7).

(D) A compressed standard concave tablet form with bisecting line, containing 50 mg. acetazolamide plus 0.25 mg. reserpine:

Gm./tab.

Acetazolamide .granulation 0.11380 White blank granulation 0.05500 Corn starch 0.00500 Reserpine 0.00025 Magnesium stearate 0.00050 See footnotes 1 and 2 under paragraph (J).

(E) A compressed A standard concave tablet form with bisecting line, containing 50 mg. acetazolamide plus 250 mg. of 7-chloro-6-sulfamyl-4-quinazolinone:

Gin/tab. Acetazolamide granulation 0.11380 White blank granulation 0.05500 Corn starch 0.00500 7-chloro-6-sulfamyl-4-quinazolinone 0.25000 Magnesium stearate 0.00050 See footnotes 1 and 2 under paragraph (J).

(F) A compressed 7 standard concave tablet form with bisecting line, containing 50 mg. acetazolamide plus 50 mg. 1,2,3,4-tetrahydro-7-chloro-2-ethyl-6-sulfamyl-4- quinazolinone:

with bisecting line, containing 50 mg. acetazolamide plus 50 mg. 1,2,3,4-tetrahydro-7-chloro-2-chloromethyl-6-sulfamyl-4-quinazolinone:

Gm./tab. Acetazolamide granulation 1 0.11380 White blank granulation 0.05500 Corn starch 0.00500 1,2,3,4 tetrahydro 7 chloro 2 chloro methyl-6-sulfamyl-4-quinazolinone 0.05000 Magnesium steararte 0.00050 See footnotes 1 and 2 under paragraph (3).

(H) A compressed standard concave tablet form with bisecting line, containing 50 mg. acetazolamide plus 0.5 mg. reserpine plus 250 mg. 7-chloro-6-sulfamyl-4- quinazolinone:

See footnotes 1 and 2 under paragraph (J).

(I) A compressed standard concave tablet form with bisecting line, containing 50 mg. acetazolamide plus 0.5 mg. reserpine plus 50 mg. 1,2,3,4-tetrahydro-7-chloro- Z-ethyl-6-sulfamyl-4-quinazolinone:

G=m./tab. Acetazolamide granulation 0.11380 White blank granulation 2 0.05500 Corn starch 0.0 0500 Reserpine 0.00050 1,2,3,4 tetrahydro 7 chloro 2 ethyl 6- sulfamyll-quinazolinone 0.05000 Magnesium stearate 0.00050 See footnotes 1 and 2 under paragraph (.1).

(J) A compressed V 5 standard concave tablet form with bisecting line, containing 50 mg. acetazolamide plus 0.5 mg. reserpine plus 50 mg. 1,2,3,4-tetrahydro-7-chloro- 2-chloromethyl-6-sulfamy1-4-quinazolinone:

Gun/tab. Acetazolamide granulation 0.11380 White blank granulation 0.05500 Corn starch 0 .00500 Reserpine 0.00050 l,2,3,4 tetrahydro 7 chloro 2 chloromethyl-6-sulfamyl-4-quinazolinone 0.05000 Magnesium stearate 0.00050 Acetarolannide granulation is compounded as follows:

Percent Acetazolamide 43.92 Algintic acid "1.76 Gelatin 1.76 \Vhi-te blank 51.27 Magnesium stearate 0.36 ater 0.93

100.00 White blank granulation is formulated as follows:

Percent Corn starch (for mixing) 18.88 Corn starch (for paste) 3.20 Dicalcium phosphate 70.53 Gum acacia 1.39

100.00 EXAMPLE 2 Acetazolamide Potentiation of the Hypotensor Activity of Reserpine The potentiation of reserpine by acetazolamide was determined quantitatively by animal tests. This correlates well with human results but exact figures are difiicult to obtain in human tests because of the impossibility of subjecting patients to specialized test conditions.

The test was made for four weeks, five days per week, on a group of metacorticoid hypertensive rats; employing oral administration of test compounds. Systolic blood pressure was taken at the end of the fourth week. The values are as follows:

Blood pres- Compound sure (systolic) mm. Hg

Controls. 212 Reserpine (10 rngJkg.) 1S8 Acetazolarnide (250 lug/kg.) 182 Acetazolamide (250 mgJkg.) plus Reserpine (10 mg./kg.) 136 6 It will be noted that there is a marked potentiation; the drop of blood pressure for the composition is greater, as compared to either drug alone, than the drug from the controls.

EXAMPLE 3 Acetazolamide Potentiation of the Diuretic Activity of 1,2,3,4 Tetrahydro 7 Chloro 2 Ethyl 6 Sulfamyl-4-Quinazolin0ne Acetazolamide potentiation of 1,2,3,4-tetrahydro-7- chloro-Z-ethyl-6-sulfamyl-4-quinazolinone (Cl 36,010) induced chloruresis and an increase in the ratio of natruresis to kaluresis were demonstrated in hydrated female dogs. The following urine electrolyte values were recorded six hours after oral dosing:

EXAMPLE 4 Acetazolamide Potentiation of the Diuretic Activity of 7-Chl0r0-6-Sulfamyl-4-Quinazolin0ne Acetazolamide potentia-ted 7-chloro-6-sulfamyl-4-quinazolinone (Cl 30,319) induced chloruresis and an increase in the ratio of natruresis to kaluresis were demonstrated in hydrated female dogs. The following urine electrolyte values were recorded six hours after oral dosing:

Compound 01-, Na+, K

meq. meq. meq.

Controls 3. 1 2. 5 4. 1 0130,319 (5 rug/kg.) 1.1 1. 4 3.1 Acetazolamide (1 rug/kg.) 1. 7 1.0 3. 3 Acetazolamide (1 mgJkg.) plus 01 30 319 (5 Ina/kg.) 19. 4 25. 9 5. 8

It will be noted that in the small doses used (5 mg./kg.), the quinazolinone compound is not an effective diuretic any more than the small amounts of the acetazollamide. On the other hand, in the small doses the qninazolinone compound also does not show serious kal uresis although, as pointed out above, when these compounds are used in large doses suflicient to be effective diuretics, the kialuresis is too high for best results. With the acetazolamide, the potentiation is spectacular and even greater than in EX- arnple 3 where the acetazolarnide was used with a diuretic which is extremely effective even in the small doses employed. There has been only a slight increase in kaluresis which remains well below the point at which there is any damage.

7 EXAMPLE 5 Acetazolamide Potentiation of the Diuretic Activity of 1,2,3,4 Tetrahydro 7 Chloro 2 Chloromethyl 6 Sulfamyl-4-Quinaz0lin0ne Acetazolamide potentiated of 1,2,3,4-tetrahydro-7-chloro 2 chloromethyl 6 sulfamyl 4 quinazolinone (Cl 100,516) induced chloruresis and an increase in the ratio of natruresis to kaluresis were remonstrated in hydrated female dogs. The following urine electrolyte values were recorded six hours after oral dosing:

Compound (31-, Na+, K+,

meq. meq. meq.

Controls 3.1 2. 8 3.0 Cl 100,516 (1 rug/kg) 17.1 18. 8 9. 4 Aeetazolarnide (1 High; 1. 7 3. 4 6. 5 Acetazolamide (1 rug/kg.) plus C1 100,516 (1 rug/kg.) 20. 8 23. 0. 9

EXAMPLE 6 Dichlorophenamide Potentiation of the Diuretic Activity of 7-ChI0r0-6-Sulfamyl-4-Quinaz0lin0ne Dichlorophenamide potentiated of 7-chloro-6-sulfamyl- 4-quinazolinone (C1 30,319) induced chloruresis and an increase in the ratio of natruresis to kaluresis were demonstrated in hydrated female dogs. The following urine electrolyte values were recorded six hours after oral dosing.

Compound 01-, Na K+,

meq rneq mcq.

Controls 3. 1 2. 8 3.0 Cl 30,319 rug/kg.) 1. 4 1. 2 3.0 Dichlorphenamide (1 nigjk 5. 7 11.3 8. 0 Dichlorphenamide (1 mg./kg.) plus C1 3 19 (5 mgJkg.) 9.0 10. 7 9. 4

EXAMPLE 7 Ethoxyzolamide Potentiation of the Diuretic Activity of 1,2,3,4 Tctrahydro 7 Chloro 2 Clzloromethyl 6 Sulfamyl-4-Quinazolin0ne Ethoxyzolamide potentiated of 1,2,3,4 tetrahydro 7 8 chloro 2 chloromethyl 6 sulfamyl 4 quinazolinoue (Cl 100,516) induced chloruresis was demonstrated in hydrated female dogs. The following electrolyte values were recorded six hours and twenty-four hours after oral administration:

6 HOURS AFTER ADMINISTRATION Compound 01-, Ne K+, meq. meq meq Controls 3. 1 2. 8 3.0 Cl100,516(1 mg./kg.). 17.1 18.8 9. 4 Ethoxyzolamide (1 nag/kg.) 4. 7 12. 8 4. 7 Ethoxyzolamido (1 rug/kg.) plus Cl 100,510

(1 mgJkg.) 20.0 15. 2 8.0

24 HOURS AFTER ADMINISTRATION Compound 01-, Not K moq. Ineq meq Controls 6. 3 8.1 8.0 Cl 100,516 (1 nigh/kg.) 26.3 27.2 18. 8 Ethoxyzolarnide (1 rug/kg.) 7. 7 18. 9 7. 7 Ethoxyzolamide (1 rug/kg.) plus C1 100,516

(1 rug/kg.) 42. 8 31. 9 25. 7

It will be noted that in six hours there is but little potentiation but at twenty-four hours the chloruresis potentiation is enormous. This example shows tremendous diuretic activity but in view of the fact that the activity is so high it shows that even smaller doses may be used with adequate results.

We claim:

1. A composition of matter comprising a mixture of acetazolamide and a 1,2,3,4 tetrahydro-7-halo-6-sulfamyl- 4-quinazolinone in the proportion of 1:1 to 1:5.

2. A composition according to claim 1 in which the 7-halo-6-sulfamyl-4-quinazolinone is 7-chloro-6-sulfamyl- 4-quinazolinone.

3. A composition according to claim 1, which contains from 0.1 to 10% of a Rauwolfia alkaloid, based on the Weight of the .acetazolamide.

4. A composition according to claim 3 in which the Rauwolfia alkaloid is reserpine.

References Cited in the file of this patent Moyer et al., Maryland MJ. 7 (10), October 1958, Diuretic Therapy: Similarities and Differences Between Chlorothiazide and Other Carbonic Anhydrase Inhibitors, pp. 574-586.

Current List Medical Literature, index volume 35, June 1959, entry Acetazolamide, p. 5-5.

Freis et al., ].A.M.A. 166:2, pp. 137-140, January 11, 1958.

New England J.M. 26 (1), January 1959, pp. 2830. 

1. A COMPOSITION OF MATTER COMPRISING A MIXTURE OF ACETAZOLAMIDE AND 1,2,3,4-TETRAHYDRO-7-HALO-6-SULFAMYL4-QUINAZOLINONE IN THE PROPORTION OF 1:1 TO 1:5. 